Adenosine is known to be an endogenous modulator of a number of physiological functions. At the cardiovascular system level, adenosine is a strong vasodilator and a cardiac depressor. On the central nervous system, adenosine induces sedative, anxiolytic and antiepileptic effects. On the respiratory system, adenosine induces bronchoconstriction. At the kidney level, it exerts a biphasic action, inducing vasoconstriction at low concentrations and vasodilation at high doses. Adenosine acts as a lipolysis inhibitor on fat cells and as an antiaggregant on platelets.
Adenosine action is mediated by the interaction with different membrane specific receptors which belong to the family of receptors coupled with G proteins. Biochemical and pharmacological studies, together with advances in molecular biology, have allowed the identification of at least four subtypes of adenosine receptors, i.e., adenosine A1, A2A, A2B and A3 receptors, of which the A1 and A2A receptors are of high-affinity and the A2B and A3 receptors are of low-affinity. The A1 and A3 receptors inhibit the activity of the enzyme adenylate cyclase, whereas the A2A and A2B receptors stimulate the activity of the same enzyme. Analogs of adenosine able to interact as antagonists with the A1, A2A, A2B and A3 receptors have been identified.
Selective antagonists for the A2A receptor are of pharmacological interest because of their reduced level of side effects. In the central nervous system, A2A antagonists can have antidepressant properties and stimulate cognitive functions. Moreover, data has shown that A2A receptors are present in high density in the basal ganglia, known to be important in the control of movement. Hence, A2A antagonists can improve motor impairment due to neurodegenerative diseases such as Parkinson's disease, senile dementia as in Alzheimer's disease, psychoses and stroke. Furthermore, A2A antagonists may be employed for the treatment of attention related disorders such as attention deficit disorder (ADD) and attention deficit hyperactivity disorder (ADHD), extra pyramidal syndrome, e.g., dystonia, akathisia, pseudoparkinsonism and tardive dyskinesia, and disorders of abnormal movement such as restless leg syndrome (RLS) and periodic limb movement in sleep (PLMS) as disclosed in WO 02/055083, WO 05/044245 and WO 06/132275. U.S. Patent Application Publication No. 2007037033 discloses adenosine A2A antagonists as useful agents for the treatment of amyotrophic lateral sclerosis. WO 01/058241 discloses the treatment of cirrhosis, and fibrosis and fatty liver by employing adenosine A2A antagonists. WO 06/009698 describes adenosine A2A antagonists as useful for the mitigation of addictive behavior. Recently, Chan et al. have demonstrated (Arthritis & Rheumatism, 54(8), 2632-2642, 2006) that adenosine A2A antagonists may be employed for the treatment and prevention of dermal fibrosis in diseases such as scleroderma.
Certain triazolopyrimidine derivatives have been disclosed previously as adenosine A2A receptor antagonists, e.g., those as described in WO 95/01356, U.S. Pat. No. 5,565,460, WO 97/05138, WO 98/52568, WO 01/92264, WO 03/032996, and WO 05/103055.